Impaired Autophagy in APOE4 Astrocytes

Shira Simonovitch, Eran Schmukler, Alina Bespalko, Tal Iram, Dan Frenkel, David M. Holtzman, Eliezer Masliah, Danny M. Michaelson, Ronit Pinkas-Kramarski

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination ofAβ plaques from isolated brain sections of transgenic 5xFADmice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

Original languageEnglish
Pages (from-to)915-927
Number of pages13
JournalJournal of Alzheimer's Disease
Volume51
Issue number3
DOIs
StatePublished - 30 Mar 2016

Keywords

  • Alzheimer's disease
  • amyloid-β
  • apolipoprotein E4
  • autophagy

Fingerprint

Dive into the research topics of 'Impaired Autophagy in APOE4 Astrocytes'. Together they form a unique fingerprint.

Cite this